T-bet Deficiency Facilitates Airway Colonization byMycoplasma pulmonisin a Murine Model of Asthma

Abstract

Epidemiological and clinical evidence suggest a correlation between asthma and infection with atypical bacterial respiratory pathogens. However, the cellular and molecular underpinnings of this correlation remain unclear. Using the T-bet-deficient (T-bet−/−) murine model of asthma and the natural murine pathogen Mycoplasma pulmonis, we provide a mechanistic explanation for this correlation. In this study, we demonstrate the capacity of asthmatic airways to facilitate colonization by M. pulmonis and the capacity of M. pulmonis to exacerbate symptoms associated with acute and chronic asthma. This mutual synergism results from an inability of T-bet−/− mice to mount an effective immune defense against respiratory infection through release of IFN-γ and the ability of M. pulmonis to trigger the production of Th2-type cytokines (e.g., IL-4 and IL-5), and Abs (e.g., IgG1, IgE, and IgA), eosinophilia, airway remodeling, and hyperresponsiveness; all pathophysiological hallmarks of asthma. The capacity of respiratory pathogens such as Mycoplasma spp. to dramatically augment the pathological changes associated with asthma likely explains their association with acute asthmatic episodes in juvenile patients and with adult chronic asthmatics, >50% of whom are found to be PCR positive for M. pneumoniae. In conclusion, our study demonstrates that in mice genetically predisposed to asthma, M. pulmonis infection elicits an inflammatory milieu in the lungs that skews the immune response toward the Th2-type, thus exacerbating the pathophysiological changes associated with asthma. For its part, airways exhibiting an asthmatic phenotype provide a fertile environment that promotes colonization by Mycoplasma spp. and one which is ill-equipped to kill and clear respiratory pathogens.

T-bet Regulates Immunity to Francisella tularensis Live Vaccine Strain Infection, Particularly in Lungs

“…Similar to LVS-infected T-bet-KO mice, T-bet-KO mice infected with T. cruzi produced IFN-␥ and IL-17. Infection of T-bet-KO mice with Mycoplasma pulmonis resulted in increased IFN-␥ levels in lungs early during M. pulmonis infection compared to the levels in infected WT mice (day 1), and the levels of IFN-␥ in lungs were equal to those in the lungs of infected WT mice on days 3 and 7 (20). In addition to T-bet, IFN-␥ production is regulated by eomesodermin (Eomes) in both CD8 ϩ and CD4 ϩ cells (29).…”

“…Many infection models demonstrate increased susceptibility in T-bet-knockout (KO) mice, including the Leishmania species Leishmania donovani (17) and L. major (11), Mycobacterium tuberculosis (18), Salmonella enterica serovar Typhimurium (19), and Mycoplasma pulmonis (20). The mechanism underlying increased susceptibility appears to depend on the model; for example, following L. major infection, T-bet-KO mice exhibited increased levels of Th2 cytokines, such as interleukin-4 (IL-4) and IL-5 (11), while during M. tuberculosis infection, CD4…”

Respiratory Tract Infection withMycoplasma pneumoniaein Interleukin-12 Knockout Mice Results in Improved Bacterial Clearance and Reduced Pulmonary Inflammation

“…Additionally, other Th1-and/or Th2-related investigations have been performed in IL-4 KO, IFN-␥ KO, and T-bet KO mice, as well as in mice depleted of CD8 T cells or CD4 T cells (2,23,43). Chu and coworkers found that when M. pneumoniae infection occurred after ovalbumin sensitization and challenge, increased IL-4 concentrations in BAL fluid and increased histologic lung inflammation were observed compared with sham-infected mice (7).…”

Role of IFN-α/β signaling in the prevention of genital herpes virus type 2 infection

“…However, the spontaneously developed asthma symptoms are explained by Mycoplasma pulmonis colonization of the airways of T-bet-deficient mice, and is associated with high bacterial loads and decreased IFN-γ responses, which triggers a Th2 response with asthma associated-symptoms (Bakshi et al, 2006). CANCER T-bet is frequently expressed in both normal lymphocytes and tumor cells.…”